Each year in the U.S., 230,000 women are diagnosed with breast cancer and 40,000 women die of it; 21,000 women are diagnosed with ovarian cancer and 14,000 women die of it; family history is one of the most important risk factors for each of these cancers, yet most of that risk remains unexplained. I have been wrestling with this problem my entire scientific life. The discoveries of BRCA1 and BRCA2, their characterization, and the translation of these discoveries to clinical practice have unquestionably made a difference. This proposal is my plan to identify the genetic causes of inherited breast cancer in those families that remain unsolved. My hypothesis is that the remaining genetic predisposition to breast and ovarian cancer is due to many different, individually rare mutations of severe effect. I suggest that some of these mutations lie in distant regulatory regions of known breast and ovarian cancer genes: the coding sequences and the close-in regions having already been thoroughly screened in our studies. I further suggest that other mutations likely alter genes not yet known to be involved in inherited predisposition to these cancers. I propose to identify these mutations, the genes that harbor them, and the mechanisms by which they act. My approach will be to integrate whole genome sequencing with application and development of bioinformatics tools and with experimental biology. I propose to address the problem from three directions simultaneously: * Discovery of new mutational mechanisms and new genes in extended kindreds severely affected by breast or ovarian cancer with normal sequences of all known breast and ovarian cancer genes * Discovery of founder mutations in young-onset breast cancer patients of Ashkenazi Jewish ancestry who have normal sequences of all known breast and ovarian cancer genes, then comparing the frequencies of potentially critical founder alleles in independent AJ cases and AJ population controls * Discovery of new candidate genes revealed by somatic mutation signatures characteristic of BRCA1, BRCA2, and perhaps other genes involved in homologous recombination, in ovarian, fallopian tube, and peritoneal cancer specimens from patients already evaluated for germline mutations in known ovarian cancer genes In addition to me, the investigators undertaking this effort are young geneticists, bioinformaticists, molecular biologists, and surgical oncologists. Our partners in whole genome sequencing are the Baylor College of Medicine Human Genome Sequencing Center. Our shared goal is to provide the information necessary to enable all genes with mutations responsible for inherited breast and ovarian cancer to be integrated into clinical practice